Malaria in pregnant women has devastating effects on the fetus and infant, resulting in abortions, premature deliveries, intrauterine growth retardation, failure to thrive, infant mortality and congenital infection. The long term objective of this proposal is to clarify the pathogenesis of malaria in pregnancy so that effective interventions that prevent these complications can be devised. The specific aims are to determine the effects of parity and prior exposure to Plasmodium on the course, severity, and outcome of clinical malaria in the mother, fetus, and newborn and to test the hypothesis that macrophage-induced cytokine imbalance causes morphologic and physiologic placental lesions that result in fetal damage, post-natal failure to thrive, and congenital infection. We have developed an animal model utilizing pregnant rhesus monkeys infected with Plasmodium coatneyi with which to study this problem. Using this model, four groups of eight rhesus monkeys will be studied. These will be nulliparous primagravida, secundigravida or multigravida animals. The monkeys will be time-bred and inoculated with Plasmodium coatneyi during the first trimester of pregnancy. After delivery, the mothers will be treated for malaria. In the second and third years, these same animals will be bred again and reinoculated with Plasmodium, with each animal and group serving as its own control. Animals will be non- immune, or have one or two previous exposures to Plasmodium. This design will allow us to examine the effects of parity and prior exposure to Plasmodium on fetal/infant outcome. Infants will be delivered by cesarean section so that placental tissues can be collected from all animals. The placentas will be examined by RT- PCR, immunohistochemistry, and in situ hybridization for cell types, cytokines, and growth factors that are important and likely to interact in placental development and malaria. The results of these studies will be correlated with histopathology of placental sections the clinical course in the mother, and the outcome of the newborn. This design will test the hypothesis that macrophages and the cytokines they produce are the likely causes of fetal injury. The information derived from these studies will allow effective interventions to be designed which will prevent the devastating effects of malaria in pregnant women and their children.